全文获取类型
收费全文 | 425篇 |
免费 | 48篇 |
专业分类
473篇 |
出版年
2019年 | 6篇 |
2018年 | 5篇 |
2017年 | 5篇 |
2016年 | 10篇 |
2015年 | 11篇 |
2014年 | 19篇 |
2013年 | 10篇 |
2012年 | 21篇 |
2011年 | 19篇 |
2010年 | 15篇 |
2009年 | 14篇 |
2008年 | 17篇 |
2007年 | 22篇 |
2006年 | 20篇 |
2005年 | 17篇 |
2004年 | 18篇 |
2003年 | 9篇 |
2002年 | 19篇 |
2001年 | 10篇 |
2000年 | 19篇 |
1999年 | 14篇 |
1998年 | 13篇 |
1997年 | 6篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 6篇 |
1991年 | 4篇 |
1990年 | 6篇 |
1989年 | 10篇 |
1988年 | 8篇 |
1987年 | 8篇 |
1986年 | 8篇 |
1985年 | 3篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 3篇 |
1979年 | 3篇 |
1976年 | 5篇 |
1975年 | 9篇 |
1973年 | 4篇 |
1971年 | 4篇 |
1970年 | 3篇 |
1968年 | 3篇 |
1951年 | 2篇 |
1949年 | 2篇 |
1935年 | 2篇 |
1930年 | 3篇 |
1907年 | 2篇 |
排序方式: 共有473条查询结果,搜索用时 9 毫秒
111.
112.
Mackay DJ Boonen SE Clayton-Smith J Goodship J Hahnemann JM Kant SG Njølstad PR Robin NH Robinson DO Siebert R Shield JP White HE Temple IK 《Human genetics》2006,120(2):262-269
The expression of imprinted genes is mediated by allele-specific epigenetic modification of genomic DNA and chromatin, including parent of origin-specific DNA methylation. Dysregulation of these genes causes a range of disorders affecting pre- and post-natal growth and neurological function. We investigated a cohort of 12 patients with transient neonatal diabetes whose disease was caused by loss of maternal methylation at the TNDM locus. We found that six of these patients showed a spectrum of methylation loss, mosaic with respect to the extent of the methylation loss, the tissues affected and the genetic loci involved. Five maternally methylated loci were affected, while one maternally methylated and two paternally methylated loci were spared. These patients had higher birth weight and were more phenotypically diverse than other TNDM patients with different aetiologies, presumably reflecting the influence of dysregulation of multiple imprinted genes. We propose the existence of a maternal hypomethylation syndrome, and therefore suggest that any patient with methylation loss at one maternally-methylated locus may also manifest methylation loss at other loci, potentially complicating or even confounding the clinical presentation.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at . 相似文献
113.
Elevated serum macrophage migration inhibitory factor (MIF) is associated with severe sepsis, but it is not clear whether bacteria stimulate synthesis of MIF by blood leukocytes directly or via induction of TNF. Here we assess production of MIF mRNA and protein by blood leukocytes from healthy human subjects (n = 28) following exposure to bacteria commonly associated with sepsis (Escherichia coli and Streptococcus pneumoniae). Bacteria did not increase levels of MIF mRNA or secreted protein. CD14+ monocytes were the main cell type producing MIF before and after stimulation. Exposure of leukocytes to TNF did not induce MIF. Hence elevated levels of serum MIF observed in sepsis may not reflect MIF produced by blood leukocytes stimulated directly by bacteria or TNF. 相似文献
114.
115.
Daniel H. Temple 《American journal of physical anthropology》2010,142(1):112-124
This study documents and interprets systemic stress during the agricultural transition in prehistoric Japan using linear enamel hypoplasia (LEH) defects and cribra orbitalia (CO) lesions. Middle to Final Jomon cultures (5000–2300 BP) from Honshu Island represent the foraging samples, while Yayoi cultures (2500–1700 BP) represent the early agricultural samples. Jomon foragers from eastern Japan had broad‐based, intensive economies. Jomon foragers from western Japan had a greater focus on seasonally available, nutritionally poor resources, while Yayoi people were descendents of migrants from the East Asian continent and introduced wet rice economies to Japan. This study tests the hypotheses that wet rice economies will be associated with a lower prevalence of teeth/individuals affected by LEH defects in western Japan, while few differences in the prevalence of teeth/individuals with LEH defects will be observed between eastern Jomon people and Yayoi farmers. It is further predicted that similar CO prevalence will be observed between Jomon and Yayoi people given environmental similarities. Significantly greater frequencies of teeth affected by LEH defects are observed among western Jomon compared to Yayoi people. The prevalence of teeth with LEH defects is slightly elevated among eastern Jomon foragers compared to Yayoi agriculturalists. Significant differences in CO prevalence are not observed. Systemic stress prevalence in western Japan likely declined following wet‐rice agriculture because this crop provided a predictable, renewable resource base. Systemic stress prevalence was similar between eastern Jomon and Yayoi people because both groups practiced intensive subsistence strategies. Similar CO prevalence reflects infectious diseases associated with living conditions. Am J Phys Anthropol, 2010. © 2009 Wiley‐Liss, Inc. 相似文献
116.
Background
Association mapping using abundant single nucleotide polymorphisms is a powerful tool for identifying disease susceptibility genes for complex traits and exploring possible genetic diversity. Genotyping large numbers of SNPs individually is performed routinely but is cost prohibitive for large-scale genetic studies. DNA pooling is a reliable and cost-saving alternative genotyping method. However, no software has been developed for complete pooled-DNA analyses, including data standardization, allele frequency estimation, and single/multipoint DNA pooling association tests. This motivated the development of the software, 'PDA' (Pooled DNA Analyzer), to analyze pooled DNA data. 相似文献117.
Indole-3-carbinol-induced death in cancer cells involves EGFR downregulation and is exacerbated in a 3D environment 总被引:3,自引:0,他引:3
Moiseeva EP Fox LH Howells LM Temple LA Manson MM 《Apoptosis : an international journal on programmed cell death》2006,11(5):799-812
Indole-3-carbinol (I3C) is a promising anticancer dietary compound, which inhibits breast cancer in animal models. The objective
of the current study was to characterize I3C-induced cell death in a panel of human breast tumorigenic cells (MCF7, MDA-MB-468,
MDA-MB-231 and HBL100) in comparison with normal fibroblasts. Since epithelial cells are protected from cell death by a three-dimensional
environment, 3D cell culture (collagen I gel and spheroids) was employed to investigate susceptibility to I3C. Cell viability
in the presence of 256 μM I3C, a concentration close to the physiologically achievable range, was in the order fibroblasts
= HBL100>MDA-MB-231>MCF7>MDA-MB-468 in monolayer culture. However, 3D culture conditions increased the susceptibility of MCF7
and MDA-MB-468 cancer cells towards I3C. I3C induced cell death in breast cancer MCF7, MDA-MB-468 and MDA-MB–231 cells via
the mitochondrial apoptotic pathway. I3C significantly reduced levels of epidermal growth factor receptor (EGFR) in MDA-MB-468
after 6 h and in MDA-MB-231 and HBL100 cells after 30 h. Downregulation of EGFR in MDA-MB468 and MDA-MB-231 cells using an
EGFR inhibitor resulted in apoptosis. EGFR modulation using EGF or an EGFR inhibitor markedly influenced viability and response
to I3C in MDA-MB-468 cells in 3D conditions. EGFR expression was modulated by 3D conditions. Therefore, I3C-induced EGFR reduction
in these cells is likely to be responsible for I3C-induced apoptosis. 相似文献
118.
119.
Maintaining the pluripotency of mouse ES cells requires both LIF (leukemia inhibitory factor) and unknown factors in serum. The paper from Ying et al. in this issue of Cell shows that BMP (bone morphogenetic protein) can replace serum in this capacity, defining molecular requirements for ES cell self-renewal. 相似文献
120.
Chaney SG Campbell SL Temple B Bassett E Wu Y Faldu M 《Journal of inorganic biochemistry》2004,98(10):1551-1559
Because of the efficacy of cisplatin and carboplatin in a wide variety of chemotherapeutic regimens, hundreds of platinum(II) and platinum(IV) complexes have been synthesized and evaluated as anticancer agents over the past 30 years. Of the many third generation platinum compounds evaluated to date, only oxaliplatin has been approved for clinical usage in the United States. Thus, it is important to understand the mechanistic basis for the differences in efficacy, mutagenicity and tumor range between cisplatin and oxaliplatin. Cisplatin and oxaliplain form the same types of adducts at the same sites on DNA. The most abundant adduct for both compounds is the Pt-GG intrastrand diadduct. Cisplatin-GG adducts are preferentially recognized by mismatch repair proteins and some damage-recognition proteins, and this differential recognition of cisplatin- and oxaliplatin-GG adducts is thought to contribute to the differences in cytotoxicity and tumor range of cisplatin and oxaliplatin. A detailed kinetic analysis of the insertion and extension steps of dNTP incorporation in the vicinity of the adduct shows that both pol beta and pol eta catalyze translesion synthesis past oxaliplatin-GG adducts with greater efficiency than past cisplatin-GG adducts. In the case of pol eta, the efficiency and fidelity of translesion synthesis in vitro is very similar to that previously observed with cyclobutane TT dimers, suggesting that pol eta is likely to be involved in error-free bypass of Pt adducts in vivo. This has been confirmed for cisplatin by comparing the cisplatin-induced mutation frequency in human fibroblast cell lines with and without pol eta. Thus, the greater efficiency of bypass of oxaliplatin-GG adducts by pol eta is likely to explain the lower mutagenicity of oxaliplatin compared to cisplatin. The ability of these cellular proteins to discriminate between cisplatin and oxaliplatin adducts suggest that there exist significant conformational differences between the adducts, yet the crystal structures of the cisplatin- and oxaliplatin-GG adducts were very similar. We have recently solved the solution structure of the oxaliplatin-GG adduct and have shown that it is significantly different from the previously published solution structures of the cisplatin-GG adducts. Furthermore, the observed differences in conformation provide a logical explanation for the differential recognition of cisplatin and oxaliplatin adducts by mismatch repair and damage-recognition proteins. Molecular modeling studies are currently underway to analyze the mechanistic basis for the differential bypass of cisplatin and oxaliplatin adducts by DNA polymerases. 相似文献